Several neurodegenerative disorders are characterized by intracellular protein accumulations or inclusion bodies, such as the Lewy bodies in Parkinson's disease. These inclusions can lead to neuronal cell death. We have studied the role of alpha- synuclein in the formation of these protein aggregates. Our data support a central role for synuclein in the pathology of several neurodegenerative diseases, and suggested that those things that accelerate the formation of aggregates or reduce their elimination could promote disease. The first test of this hypothesis was the search for mutations in the ubiquitin hydrolase gene, the product of which is responsible for liberating ubiquitin monomers from their precursor. As predicted, a family was discovered with a missense mutation in this gene. Presumably, this results in defective proteasomal function and permits damaged proteins to accumulate in cells of the substantia nigra.